Current treatments for human diseases target the disease and generally focus on eliminating the inciting agent or the symptoms, such as microbes, antigens, tumors, and pain, usually injuring healthy tissues in the process. Treatments that focus, instead, on enabling the host to treat its own disease, without toxic side effects, by supporting the host in controlling its cellular functions, are the subject of this invention, which methods of treatment comprise phthalazine dione compounds that buffer intracellular reduction and oxidation to modulate cell fates in various disease states.
In stressed cells with uncontrolled life and death cycles—as in neurodegenerative, autoimmune, hyperproliferative, hyperinflammatory, or iatrogenic diseases—the intracellular redox status deviates from its normal physiological state. In homeostasis, the intracellular redox status provides the proper environment for various cellular processes of growth, differentiation, activity, and death. An impaired or aberrant intracellular redox status, as it disables cellular processes, deprives cells of the ability to defend against stresses and therefore to survive. The maintenance of redox status is thus critical to the fate of the cell.
Any number of stresses greatly perturbs cellular redox status. Aberrant redox status results from internal causes such as defective regulatory gene products or from external causes such as radiation, chemotherapeutic agents, toxins, inflammogens, antigens, microbes, caloric excesses, oxidants, and carcinogens. As cellular redox agents become depleted during stress, cells inevitably dysfunction and die prematurely, as in Alzheimer's, AIDS, Huntington's, Parkinson's, ALS, psoriasis, and cancer.
Research has shown that alterations in cellular redox status play a role in cellular signaling, suggesting that antioxidants and sulfhydryl-reactive agents, which alter the redox status, could modulate cellular activation (see U.S. Pat. No. 5,994,402). Moreover, cellular thiols are known to be important in maintaining intracellular redox status (see U.S. Pat. No. 5,994,402). Consequently, altering the redox state of cells by depleting cellular thiol has been described as a method to reduce inflammation (see U.S. Pat. No. 5,994,402). This method, however, does not disclose use of any phthalazine compounds to maintain the cellular redox status.
Phthalazine compounds such as 5-amino-2,3-dihydro-1,4-phthalazinedione, also known as luminol, have been widely used in photothermographic imaging and in chemiluminescent labeling of cellular structures. However, their pharmacological or therapeutic use has been limited to identification as an inhibitor of poly (ADP-ribose) polymerase, an enzyme that responds to DNA damage (see U.S. Pat. Nos. 5,874,444; 5,719,151; 5,633,282), and to application in treating skin aging, Alzheimer's, atherosclerosis, osteoarthritis, osteoporosis, age-related macular degeneration, muscular dystrophy, immune senescence, viral infections, and cancer as diseases involving the functions of poly (ADP-ribose) polymerase (see U.S. Pat. Nos. 5,874,444; 5,719,151; 5,633,282).
Furthermore, although phthaloylhydrazide derivatives have been described as anti-inflammatory or anti-hypoxic agents for use in treating disorders such as ulcerative colitis, Crohn's, diffuse sclerosis, diarrhea, proctitis, hemorrhoids, anal fissures, dyspepsia, intestinal infection, proctosigmoiditis, skin irritation, and transplant rejection (see U.S. Pat. Nos. 5,543,410; 5,512,573), their role in modulating intracellular redox status and cell fates was not recognized.
Methods for correcting imbalances in cellular redox status with currently available redox agents—cysteine, reduced thiols, antioxidants, reduced lipoates, and glucocorticoids—remain inadequate, in that these agents are labile, quickly oxidized, or unable to translocate to the proper region of the cell. Redox agents that buffer cellular redox imbalances, without toxicities, and thus enable redox-stressed cells to regain control over their redox status and defense mechanisms, would be beneficial in treating diseases accompanied or marked by impaired or aberrant intracellular redox status.